Protective role of adenine nucleotide translocase in O2-deficient hearts

Abstract

At subsaturating concentrations of palmitoyl-CoA, the carnitine-dependent oxidation of the palmitoyl portion by uncoupled rat heart mitochondria was stimulated by ADP or ATP. This effect was traced to the prevention of acyl-CoA binding to adenine nucleotide translocase and the consequent sparing of acyl-CoA for acylcarnitine formation. Palmitoyl-CoA oxidation was stimulated by ITP also although ITP served neither as a transportable substrate nor as an inhibitor of ADP transport. ITP and other nontransportable nucleoside di(tri)phosphates prevented octanoyl-CoA binding to mitochondria. ITP was bound to mitochondria, and this binding was reversed by ADP, octanoyl-CoA, and carboxyatractyloside. Thus, besides a substrate site, there is a site on the translocase that binds nucleoside di(tri)phosphates, CoA and its esters, and atractylosides; inhibition of the translocase results, however, only from the binding of CoA esters of fatty acids and of atractylosides. We suggest that in O2-deficient hearts, when nucleotides decline and fatty acyl-CoA rises, the binding of the latter to the translocase becomes operational to slow fatty acylcarnitine production. By retarding the rise in amphipathic burden, this mechanism could protect heart against irreversible damage during brief periods of ischemia or hypoxia.

Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase

“…Moreover, increased levels of long chain FAs have also been suspected to be involved in unexplained sudden death in infants with conduction defects or ventricular fibrillation and tachycardia [59]. In addition to LCAC accumulation, acute ischemia is also associated with a decreased ANT activity, independently of any change in oxidative phosphorylation, [60][61][62] and an increased RyR2 oxidation leading to reperfusion injury [63]. Similarly, PC level was shown to correlate with NYHA classification and high plasma levels of PC were significantly associated with serious adverse events and poor prognostic of heart failure patients [64].…”

Malonyl-CoA binding site and the overt carnitine palmitoyltransferase activity reside on the opposite sides of the outer mitochondrial membrane.

“…Thus, Nagarse pretreatment had no noticeable effect on the carboxyatractyloside-insensitive (to eliminate contribution of the acyl-CoA binding on the adenine nucleotide translocase, the major IM binding site; ref. 36) or -sensitive binding of octanoyl-CoA to mitochondria. The latter was also not affected by the presence of malonyl-CoA.…”

Anion Carriers of Mitochondrial Membranes

“…Since adenine nucleotide transport is electrophoretic (Klingenberg, 1975), the decrease in protonmotive force following deenergisation is accompanied by a backflow of cytosolic ATP into the matrix where it is hydrolysed by H+-ATPase to restore the protonmotive force. Pande et al (1984) have suggested that adenine nucleotide translocase protects the hypoxic heart from failure by building large amounts of cytosolic LCA thus preventing the increase of mitochondrial acylcarnitine and LCA which were believed to cause mitochondrial damage. The dramatic increase in mitochondrial LCA prevents breakdown of the heart during hypoxia by inhibiting transport of ATP back into the mitochondria.…”